There is a recognized clinical need to identify new molecular therapeutic targets for advanced prostate cancers that have failed androgen ablation therapy (i.e. castration-resistant prostate cancer). Furthermore, the frequent failure in the clinial setting of cancer drugs with demonstrable activity in xenograft models makes the testing of drug candidates in autochthonous animal models imperative. The overarching goal of this research program is to develop the oncogenic serine-threonine kinase PIM1 kinase as a therapeutic target in prostate cancer. PIM1 is coexpressed with c-MYC and dramatically enhances c-MYC-driven prostate tumorigenesis in a kinase-dependent manner. Notably, PIM1 is induced in tumors by hypoxia and by treatment with docetaxel, a common but largely ineffective option for patients with advanced castration-resistant prostate cancer. PIM1 induction by hypoxia and docetaxel promotes prostate cancer cell survival and therapeutic resistance. Therefore PIM1 may represent a valuable therapeutic target in prostate cancer. To test this notion, we have developed new autochthonous mouse models of prostate cancer for testing the efficacy of novel PIM1 kinase inhibitors in treating prostate cancer and reversing therapeutic resistance. We have also identified novel candidate PIM1-interacting proteins in prostate epithelial cells. Among the proteins identified are a MYC transcriptional cofactor and a prostate stem cell marker/regulator. We hypothesize that PIM1 promotes prostate tumorigenesis by phosphorylating key substrates involved in regulating MYC transcriptional acivity and stem cell function and that targeting PIM1 kinase activity is an effective strategy to treat MYC/PIM1- expressing prostate cancer. We will address these hypotheses via three aims. In the first aim, we will elucidate the mechanistic basis for cooperativity between MYC and PIM1 in prostate cancer. In the second aim, we will investigate the role of PIM1 in regulating stem cell renewal. In the third aim, we will test the efficacy of novel PIM1 kinase inhibitors in treating prostate cancer and reversing therapeutic resistance in vivo. These studies should to provide us with novel insights into the mechanisms of PIM1 function in prostate cancer and rigorously test the effectiveness of new PIM1 kinase inhibitors in treating prostate cancer and reversing therapeutic resistance.